The present invention relates to azetidine derivatives of formula: 
their optical isomers, their salts, their preparation and medicaments containing them.
In formula (I),
R represents a chain 
R1 represents a methyl or ethyl radical,
R2 represents either an aromatic chosen from phenyl, naphthyl or indenyl, these aromatics being nonsubstituted or substituted with one or more halogens, alkyl, alkoxy, xe2x80x94COxe2x80x94alk, hydroxyl, xe2x80x94COOR5, formyl, trifluoromethyl, trifluoromethylsulfanyl, trifluoromethoxy, nitro, xe2x80x94NR6R7, xe2x80x94COxe2x80x94NHxe2x80x94NR6R7, xe2x80x94N(alk)COOR8, cyano, xe2x80x94CONHR9, xe2x80x94COxe2x80x94NR16R17, alkylsulfanyl, hydroxyalkyl, xe2x80x94Oxe2x80x94alk-NR12R13 or alkylthioalkyl or a heteroaromatic chosen from the benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzothienyl, indolinyl, isochromanyl, isoquinolyl, pyridyl, quinolyl, 1,2,3,4-tetrahydroisoquinolyl, 1,2,3,4-tetrahydroquinolyl, thiazolyl, or thienyl rings, it being possible for these heteroaromatics to be nonsubstituted or substituted with a halogen, alkyl, alkoxy, xe2x80x94COOR5, trifluoromethyl, trifluoromethylsulfanyl, trifluoromethoxy, nitro, xe2x80x94NR6R7, xe2x80x94COxe2x80x94NHxe2x80x94NR6R7, cyano, xe2x80x94CONHR9, alkylsulfanyl, hydroxyalkyl or alkylthioalkyl,
R3 and R4, which are identical or different, represent either an aromatic chosen from phenyl, naphthyl or indenyl, these aromatics being nonsubstituted or substituted with one or more halogens, alkyl, alkoxy, formyl, hydroxyl, trifluoromethyl, trifluoromethoxy, xe2x80x94CO-alk, cyano, xe2x80x94COOR5, xe2x80x94CONR10R11, xe2x80x94COxe2x80x94NHxe2x80x94NR6R7, alkylsulfanyl, hydroxyalkyl, -alk-NR6R7 or alkylthioalkyl; or a heteroaromatic chosen from benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzothienyl, furyl, isochromanyl, isoquinolyl, pyrrolyl, quinolyl, 1,2,3,4-tetrahydroisoquinolyl, thiazolyl or thienyl rings, it being possible for these heteroaromatics to be nonsubstituted or substituted with a halogen, alkyl, alkoxy, hydroxyl, trifluoromethyl, trifluoromethoxy, cyano, xe2x80x94COOR5, xe2x80x94COxe2x80x94NHxe2x80x94NR6R7, xe2x80x94CONR10R11, -alk-NR6R7, alkylsulfanyl, hydroxyalkyl or alkylthioalkyl;
R5 is an alkyl or phenyl radical which is optionally substituted with one or more halogen atoms,
R6 and R7, which are identical or different, represent a hydrogen atom or an alkyl, xe2x80x94COOalk, cycloalkyl, alkylcycloalkyl, -alk-O-alk or hydroxyalkyl radical or alternatively R6 and R7 together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated or unsaturated mono- or bicyclic heterocycle optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl, xe2x80x94COalk, xe2x80x94COOalk, xe2x80x94COxe2x80x94NHalk, xe2x80x94CSxe2x80x94NHalk, xe2x80x94CO-alk-NR14R15, oxo, hydroxyalkyl, -alk-O-alk or xe2x80x94COxe2x80x94NH2 radicals,
R8 represents an alkyl radical,
R9 represents a hydrogen atom or an alkyl radical or an alkyl radical substituted with a dialkylamino, phenyl, cycloalkyl (optionally substituted with xe2x80x94COOalk) or a 3- to 10-membered saturated or unsaturated mono- or bicyclic heterocycle optionally containing one or more heteroatoms chosen from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl radicals,
R10 and R11, which are identical or different, represent a hydrogen atom or an alkyl radical or alternatively R10 and R11 together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated mono- or bicyclic heterocycle optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with an alkyl radical,
R12 and R13, which are identical or different, represent hydrogen atom or an alkyl or cycloalkyl radical or alternatively R12 and R13 together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated mono- or bicyclic heterocycle optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with an alkyl, xe2x80x94COalk, xe2x80x94COOalk, xe2x80x94COxe2x80x94NHalk, xe2x80x94CSxe2x80x94NHalk or xe2x80x94CO-alk-NR14R15 radical or a 3- to 10-membered saturated mono- or bicyclic heterocycle containing a heteroatom chosen from oxygen, sulfur and nitrogen,
R14 and R15, which are identical or different, represent a hydrogen atom or an alkyl or xe2x80x94COOalk radical,
R16 and R17 together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated mono- or bicyclic heterocycle optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen,
Rxe2x80x2 represents a hydrogen atom or a xe2x80x94CO-alk radical, alk represents an alkyl or alkylene radical.
In the preceding definitions and in those which follow, unless otherwise stated, the alkyl and alkylene radicals and portions and the alkoxy radicals and portions are in the form of a straight or branched chain and contain 1 to 6 carbon atoms.
Among the alkyl radicals, there may be mentioned methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl and hexyl radicals. Among the alkoxy radicals, there may be mentioned methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy and pentyloxy radicals.
The term halogen comprises chlorine, fluorine, bromine and iodine.
When R2 and/or R3 and/or R4 represent independently a substituted phenyl, the latter is preferably mono-, di- or trisubstituted.
When R6 and R7 together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated or unsaturated mono- or bicyclic heterocycle, the latter is preferably an azetidinyl, pyrrolidinyl, piperazinyl, piperidyl, morpholinyl, imidazolyl, thiomorpholinyl or furyl ring, these rings being optionally substituted with an alkyl, hydroxyalkyl, -alk-O-alk, xe2x80x94CONH2, xe2x80x94COalk, xe2x80x94COOalk, oxo, xe2x80x94CSNHalk, xe2x80x94CONHalk or xe2x80x94CO-alk-NR14R15 radical and, in particular, with a methyl, ethyl, propyl, isobutyl, acetyl, N,N-dimethylaminomethylcarbonyl, methyloxycarbonyl, methylcarbamoyl, methylthiocarbamoyl, N-methylaminomethylcarbonyl, N-methyl-N-tertbutoxycarbonylaminomethylcarbonyl, oxo, xe2x80x94CSNHCH3 or xe2x80x94CONHCH3 radical.
When R10 and R11 together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated mono- or bicyclic heterocycle, the latter is preferably an azetidinyl, pyrrolidinyl, piperazinyl, piperidyl, morpholinyl or thiomorpholinyl ring, these rings being optionally substituted with an alkyl.
When R12 and R13 form together with the nitrogen atom to which they are attached a 3- to 10-membered saturated mono- or bicyclic heterocycle, the latter is preferably an azetidinyl, pyrrolidinyl, piperazinyl, piperidyl, morpholinyl or thiomorpholinyl ring, these rings being optionally substituted with an alkyl, xe2x80x94COalk, xe2x80x94COOalk, xe2x80x94COxe2x80x94NHalk, xe2x80x94CSxe2x80x94NHalk or xe2x80x94CO-alk-NR14R15 radical or a 3- to 10-membered saturated mono- or bicyclic heterocycle containing a heteroatom chosen from oxygen, sulfur and nitrogen, and, in particular, with a thiomorpholinyl radical.
When R16 and R17 together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated mono- or bicyclic heterocycle, the latter is preferably a piperidyl ring.
When R9 represents an alkyl radical substituted with a 3- to 10-membered saturated or unsaturated mono- or bicyclic heterocycle optionally containing one or more heteroatoms chosen from oxygen, sulfur and nitrogen, the latter is preferably a pyrrolidinyl, tetrahydrofuryl, morpholinyl or pyrrolyl ring, these rings being optionally substituted with one or more alkyl radicals.
The compounds of formula (I) may be provided in the form of enantiomers and diastereoisomers. These optical isomers and mixtures thereof form part of the invention.
The compounds of formula (I) for which R represents a chain of formula (A) may be prepared by dehydration of a corresponding compound of formula (Ia) 
in which R1, R2, R3 and R4 have the same meanings as in formula (I) and Rxe2x80x3 represents a hydroxyl, methanesulfonyloxy or acetyloxy radical.
This dehydration is carried out by any method known to persons skilled in the art which makes it possible to dehydrate an alcohol or one of its derivatives in order to obtain the corresponding alkene. Preferably, derivatives are used for which Rxe2x80x3 is a methanesulfonyloxy or acetyloxy radical obtained from the corresponding derivative for which Rxe2x80x3 is a hydroxyl radical by the action of methanesulfonyl chloride or acetyl chloride, in an inert solvent such as pyridine, tetrahydrofuran, dioxane, a chlorinated solvent (dichloromethane or chloroform for example), at a temperature of between 5xc2x0 C. and 20xc2x0 C. and then the medium is treated with a base such as an alkali metal hydroxide (sodium hydroxide for example), an alkali metal carbonate (sodium or potassium carbonate for example), an amine such as a trialkylamine (triethylamine for example), 4-dimethylaminopyridine, diaza-1,8-bicyclo[5.4.0]undec-7-ene, at a temperature of between 0xc2x0 C. and the boiling temperature of the reaction mixture. The methanesulfonyloxy and the acetyloxy may be isolated or otherwise.
The compounds of formula (I) for which R represents a chain (B) in which Rxe2x80x2 is a hydrogen atom may be prepared by reacting the derivative R1SO2CH2R2 (II) for which R1 and R2 have the same meanings as in formula (I) with an azetidinone of formula: 
in which R3 and R4 have the same meanings as in formula (I).
The procedure is generally carried out in an inert solvent such as an ether (tetrahydrofuran for example), in the presence of a strong base such as lithium diisopropylamide, potassium tert-butoxide or n-butyllithium, at a temperature of between xe2x88x9270xc2x0 C. and xe2x88x9215xc2x0 C.
The derivatives of formula (II) may be obtained by application or adaptation of the methods described in the examples. In particular, the procedure is carried out according to the following reaction schemes: 
In these formulae Hal represents a halogen atom and, preferably, chlorine, bromine or iodine, R1 and R2 have the same meanings as in formula (I).
The reaction (a) is generally carried out in an inert solvent such as dimethylformamide or a 1-4C aliphatic alcohol, at a temperature of between 20 and 30xc2x0 C.
The reaction (b) is carried out by any known method which makes it possible to oxidize a sulfur-containing derivative without affecting the rest of the molecule such as the methods described by M. HUDLICKY, Oxidations in Organic Chemistry, ACS Monograph, 186, 252-263 (1990). For example, the procedure is carried out by the action of an organic peroxy acid or a salt of such a peroxy acid (peroxycarboxylic or peroxysulfonic acids, especially peroxybenzoic acid, 3-chloroperoxybenzoic acid, 4-nitroperoxybenzoic acid, peroxyacetic acid, trifluoroperoxyacetic acid, peroxyformic acid or monoperoxyphthalic acid) or in organic peracids or a salt of such an acid (for example periodic or persulfuric acid), in an inert solvent such as a chlorinated solvent (chloroform or dichloromethane for example), at a temperature of between 0 and 25xc2x0 C. It is also possible to use hydrogen peroxide or a periodate (sodium periodate for example), in an inert solvent such as 1-4C aliphatic alcohol (methanol or ethanol for example), water or a mixture of these solvents, at a temperature of between 0 and 20xc2x0 C. It is also possible to carry out the procedure using tert-butyl hydroperoxide in the presence of titanium tetraisopropoxide in a 1-4C aliphatic alcohol (methanol or ethanol for example) or a water-alcohol mixture, at a temperature close to 25xc2x0 C. or using oxoneR(potassium peroxymonosulfate), in a 1-4C aliphatic alcohol (methanol or ethanol for example), in the presence of water, acetic acid or sulfuric acid, at a temperature close to 20xc2x0 C.
The reaction (c) is preferably carried out in an inert solvent such as a 1-4C aliphatic alcohol (methanol or ethanol for example), at a temperature of between 20xc2x0 C. and the boiling temperature of the reaction medium.
The derivatives of formula (IV) are commercially available or may be obtained by application or adaptation of the methods described in the examples. In particular, the methylated derivative or the corresponding alcohol is halogenated using a halogenating agent such as hydrobromic acid, in acetic acid, at a temperature close to 20xc2x0 C. or N-bromo- or chlorosuccinimide in the presence of benzoyl peroxide, in an inert solvent such as tetrachloromethane, at the boiling temperature of the reaction medium. The methylated derivatives or the corresponding alcohols are commercially available or may be obtained according to the methods described by BRINE G. A. et al., J. Heterocycl. Chem., 26, 677 (1989) and NAGARATHNAM D., Synthesis, 8, 743 (1992) and in the examples.
The azetidinones of formula (III) may be obtained by application or adaptation of the methods described by KATRITZKY A. R. et al., J. Heterocycl. Chem., 271 (1994) or DAVE P. R., J. Org. Chem., 61, 5453 (1996) and in the examples. The procedure is generally carried out according to the following reaction scheme: 
In these formulae, R3 and R4 have the same meanings as in formula (I) and X represents a chlorine or bromine atom.
In step A, the procedure is preferably carried out in an inert solvent such as a 1-4C aliphatic alcohol (ethanol or methanol for example), optionally in the presence of an alkali metal hydroxide, at the boiling temperature of the reaction medium.
In step B, the reduction is generally carried out using lithium aluminum hydride, in tetrahydrofuran at the boiling temperature of the reaction medium.
In step C, the procedure is preferably carried out in an inert solvent such as a 1-4C aliphatic alcohol (ethanol or methanol for example) in the presence of sodium hydrogen carbonate, at a temperature of between 20xc2x0 C. and the boiling temperature of the reaction medium.
In step D, the oxidation is preferably carried out in DMSO, using the sulfurtrioxide-pyridine complex, at a temperature close to 20xc2x0 C. or using dimethyl sulfoxide, in the presence of oxalyl chloride and triethylamine, at a temperature of between xe2x88x9270 and xe2x88x9250xc2x0 C.
In step E, the procedure is carried out according to the method described by GRISAR M. et al., in J. Med. Chem., 885 (1973). The magnesium compound of the brominated derivative is formed and then the nitrile is reacted, in an ether such as ethyl ether, at a temperature of between 0xc2x0 C. and the boiling temperature of the reaction medium. After hydrolysis with an alcohol, the intermediate imine is reduced in situ with sodium borohydride at a temperature of between 0xc2x0 C. and the boiling temperature of the reaction medium.
The R3xe2x80x94COxe2x80x94R4 derivatives are commercially available or may be obtained by application or adaptation of the methods described by KUNDER N. G. et al. J. Chem. Soc. Perkin Trans 1, 2815 (1997); MORENO-MARRAS M., Eur. J. Med. Chem., 23 (5) 477 (1988); SKINNER et al., J. Med. Chem., 14 (6) 546 (1971); HURN N. K., Tet. Lett., 36 (52) 9453 (1995); MEDICI A. et al., Tet. Lett., 24 (28) 2901 (1983); RIECKE R. D. et al., J. Org. Chem., 62 (20) 6921 (1997); KNABE J. et al., Arch. Pharm., 306 (9) 648 (1973); CONSONNI R. et al., J. Chem. Soc. Perkin Trans 1, 1809 (1996); FR-96-2481 and JP-94-261393.
The R3Br derivatives are commercially available or may be obtained by application or adaptation of the methods described by BRANDSMA L. et al., Synth. Comm., 20 (11) 1697 and 3153 (1990); LEMAIRE M. et al., Synth. Comm., 24 (1) 95 (1994); GODA H. et al., Synthesis, 9 849 (1992); BAEUERLE P. et al., J. Chem. Soc. Perkin Trans 2, 489 (1993).
The R4CN derivatives are commercially available or may be obtained by application or adaptation of the methods described by BOUYSSOU P. et al., J. Het. Chem., 29 (4) 895 (1992); SUZUKI N. et al., J. Chem. Soc. Chem. Comm., 1523 (1984); MARBURG S. et al., J. Het. Chem., 17 1333 (1980); PERCEC V. et al., J. Org. Chem. 60 (21) 6895 (1995).
The compounds of formula (I) for which R represents a chain (B) in which Rxe2x80x2 is a hydrogen atom may also be prepared by action of a derivative R3CH(Br)R4 (VI) for which R3 and R4 have the same meanings as in formula (I) with a derivative of formula: 
in which R1 and R2 have the same meanings as in formula (I).
This reaction is generally carried out in the presence of a base such as an alkali metal carbonate (potassium carbonate for example), in an inert solvent such as acetonitrile, at the boiling temperature of the reaction medium.
The derivatives of formula (VI) are commercially available or may be obtained by application or adaptation of the method described by BACHMANN W. E., J. Am. Chem. Soc , 2135 (1933). Generally, the corresponding alcohol R3CHOHR4 is brominated using hydrobromic acid, in acetic acid, at a temperature of between 0xc2x0 C. and the boiling temperature of the reaction medium.
The corresponding R3CHOHR4 alcohols are commercially available or may be obtained by application or adaptation of the methods described by PLASZ A. C. et al., J. Chem. Soc. Chem. Comm., 527 (1972).
The derivatives of formula (VII) may be obtained by hydrolysis of a derivative of formula: 
in which R1 and R2 have the same meanings as in formula (I).
This reaction is generally carried out using hydrochloric acid, in an inert solvent such as an ether (dioxane for example), at a temperature close to 20xc2x0 C.
The derivatives of formula (VIII) are obtained by reacting vinyl chloroformate with a corresponding compound of formula (I) for [lacuna] R represents a chain of formula (B), Rxe2x80x2 represents a hydroxyl radical, R3 and R4 are phenyl radicals, in an inert solvent such as a chlorinated solvent (dichloromethane or chloroform for example), at a temperature of between 0xc2x0 C. and the boiling temperature of the reaction mixture.
The compounds of formula (I) for which R is a chain (B) in which Rxe2x80x2 is a xe2x80x94CO-alk radical may be prepared by reacting a halide Hal-CO-alk in which Hal represents a halogen atom and, preferably, a chlorine atom and alk represents an alkyl radical with a corresponding compound of formula (I) for which R is a chain (B) in which Rxe2x80x2 is a hydrogen atom.
This reaction is generally carried out in an inert solvent such as tetrahydrofuran, dioxane, a chlorinated solvent (dichloromethane or chloroform for example), at a temperature of between xe2x88x9250xc2x0 C. and 20xc2x0 C., in the presence of n-butyllithium.
The compounds of formula (I) for which R2 represents an aromatic or a heteroaromatic substituted with xe2x80x94NR6R7 in which R6 and R7 each represent a hydrogen atom may also be prepared by reducing a corresponding compound of formula (I) for which R2 represents an aromatic or a heteroaromatic substituted with nitro.
This reaction is carried out by any known method which makes it possible to reduce a nitro to an amino without affecting the rest of the molecule. Preferably, iron is used in the presence of hydrochloric acid in a 1-4C aliphatic alcohol such as ethanol, at the boiling temperature of the reaction medium.
The compounds of formula (I) for which R2 represents an aromatic or heteroaromatic substituted with xe2x80x94COHNR9 and/or R3 and/or R4 represent an aromatic or a heteroaromatic substituted with xe2x80x94CONR10R11 may also be prepared by reacting a corresponding compound of formula (I) for which R2 and/or R3 and/or R4 represent an aromatic or a heteroaromatic substituted with xe2x80x94COOR5 for which R5 is alkyl or phenyl optionally substituted with halogens with respectively an amine H2NR9 or HNR10R11 for which R9, R10 and R11 have the same meanings as in formula (I)
This reaction is generally carried out in an inert solvent such as a chlorinated solvent (dichloromethane or chloroform for example) or a 1-4C aliphatic alcohol (methanol or ethanol for example), at a temperature of between 0xc2x0 C. and the boiling temperature of the reaction mixture.
The compounds of formula (I) for which R2 represents an aromatic substituted with hydroxyl and/or R3 and/or R4 represent an aromatic or a heteroaromatic substituted with hydroxyl may also be prepared by hydrolysis of a corresponding compound of formula (I) for which R2 represents an aromatic substituted with alkoxy and/or R3 and/or R4 represent an aromatic or a heteroaromatic substituted with alkoxy.
This reaction is carried out by any method of hydrolyzing an alkoxy to a hydroxyl without affecting the rest of the molecule. Preferably, the hydrolysis is carried out using boron tribromide, in a chlorinated solvent such as dichloromethane, at a temperature close to 20xc2x0 C.
The compounds of formula (I) for which R2 represents an aromatic substituted with xe2x80x94NR6R7 for which R6 represents an alkyl radical and R7 represents a hydrogen atom may also be prepared by deprotecting a corresponding compound of formula (I) for which R2 represents an aromatic substituted with an xe2x80x94N(alk)COOR8 in which R8 represents a tert-butyl radical.
This reaction is generally carried out using hydrochloric acid, in a solvent such as dioxane at a temperature close to 20xc2x0 C.
The compounds of formula (I) for which R2 and/or R3 and/or R4 represent an aromatic substituted with xe2x80x94COOR5 may also be prepared by esterification of a derivative of formula: 
for which R represents a chain Cxe2x95x90C(SO2R1)Rxe2x80x22 or C(ORxe2x80x2)CH(SO2R1)Rxe2x80x22, R1, Rxe2x80x22, Rxe2x80x23 and Rxe2x80x24 have the same meanings as the substituents R1, R2, R3 and R4 of formula (I) with the proviso that at least one of the substituents Rxe2x80x22, Rxe2x80x23 and Rxe2x80x24 represents an aromatic or a heteroaromatic substituted with carboxyl, using a derivative of formula R5OH for which R5 is alkyl or phenyl optionally substituted with one or more halogens.
When R5 is alkyl, this reaction is generally carried out in the presence of an inorganic acid (sulfuric acid for example), at a temperature of between 20xc2x0 C. and the boiling temperature of the reaction medium. When R5 is optionally substituted phenyl, this reaction is preferably carried out in the presence of a carbodiimide (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide or N,Nxe2x80x2-dicyclohexylcarbodiimide for example), in an inert solvent such as an imide (dimethylformamide) or a chlorinated solvent (methylene chloride, 1,2-dichloroethane or chloroform for example), at a temperature of between 0xc2x0 C. and the boiling temperature of the reaction mixture.
The derivatives of formula (IX) for which R represents a chain Cxe2x95x90C(SO2R1)Rxe2x80x22 or C(ORxe2x80x2)CH(SO2R1)Rxe2x80x22, Rxe2x80x2, R1, Rxe2x80x22, Rxe2x80x23 and Rxe2x80x24 have the same meanings as the substituents Rxe2x80x2, R1, R2, R3 and R4 of the formula (I) with the proviso that at least one of the substituents Rxe2x80x22, Rxe2x80x23 and Rxe2x80x24 represents an aromatic or a heteroaromatic substituted with carboxyl may be obtained according to the methods described above for the preparation of the compounds of formula (I) from the corresponding intermediates and in particular according to the method described in Example 29.
The compounds of formula (I) for which R2 and/or R3 and/or R4 represent an aromatic or a heteroaromatic substituted with alkylthioalkyl may also be prepared by reaction of a derivative of formula (IX) for which R represents a chain Cxe2x95x90C(SO2R1)Rxe2x80x22 or C(ORxe2x80x2)CH(SO2R1)Rxe2x80x22, Rxe2x80x2, R1, Rxe2x80x22, Rxe2x80x23 and Rxe2x80x24 have the same meanings as the substituents Rxe2x80x2, R1, R2, R3 and R4 of the formula (I) with the proviso that at least one of the substituents Rxe2x80x22, Rxe2x80x23 and Rxe2x80x24 represents an aromatic or a heteroaromatic substituted with haloalkyl with sodium alkylthiolate.
This reaction is generally carried out in an inert solvent such as an amide (dimethylformamide for example), at a temperature close to 20xc2x0 C.
The derivatives of formula (IX) for which R represents a chain Cxe2x95x90C(SO2R1)Rxe2x80x22 or C(ORxe2x80x2)CH(SO2R1)Rxe2x80x22, Rxe2x80x2, R1, Rxe2x80x22, Rxe2x80x23 and Rxe2x80x24 have the same meanings as the substituents Rxe2x80x2, R1, R2, R3 and R4 of the formula (I) with the proviso that at least one of the substituents Rxe2x80x22, Rxe2x80x23 and Rxe2x80x24 represents an aromatic or a heteroaromatic substituted with haloalkyl may be obtained by reacting a phosphorus trihalide (preferably phosphorus tribromide) with a corresponding compound of formula (I) for which R2 and/or R3 and/or R4 represent an aromatic or a heteroaromatic substituted with hydroxyalkyl, in an inert solvent such as a chlorinated solvent (carbon tetrachloride or chloroform for example), at a temperature close to 20xc2x0 C.
The compounds of formula (I) for which R2 and/or R3 and/or R4 represent an aromatic substituted with hydroxyalkyl in which the alkyl contains one carbon atom may also be prepared by reducing a compound of formula (I) for which at least one of the substituents R2, R3 and R4 represents an aromatic substituted with formyl.
This reaction is generally carried out using sodium borohydride, in a 1-4C aliphatic alcohol (methanol or ethanol for example), at a temperature close to 0xc2x0 C.
The compounds of formula (I) for which R3 and/or R4 represents an aromatic substituted with -alk-NR6R7 for which alk is an alkyl containing one carbon atom may also be prepared by reacting a compound of formula (I) for which at least one of the substituents R3 and R4 represents an aromatic substituted with formyl with an amine HNR6R7 in which R6 and R7 have the same meanings as in formula (I).
This reaction is generally carried out in an inert solvent such as a chlorinated solvent (dichloroethane for example), at a temperature close to 20xc2x0 C. in the presence of sodium triacetoxyborohydride or sodium cyanoborohydride.
The compounds of formula (I) for which R2 represents an aromatic or a heteroaromatic substituted with xe2x80x94CONHR9 and/or R3 and/or R4 represents an aromatic or heteroaromatic substituted with xe2x80x94COxe2x80x94NR10OR11 may also be prepared by reacting a derivative of formula (IX) for which R represents a chain Cxe2x95x90C(SO2R1)Rxe2x80x22 or C(ORxe2x80x2)CH(SO2R1)Rxe2x80x22, Rxe2x80x2, R1, Rxe2x80x22, Rxe2x80x23 and Rxe2x80x24 have the same meanings as the substituents Rxe2x80x2, R1, R2, R3 and R4 of the formula (I) with the proviso that at least one of the substituents Rxe2x80x22, Rxe2x80x23 and Rxe2x80x24 represents an aromatic or a heteroaromatic substituted with carboxyl with respectively an amine H2NR9 or HNR10R11 in which R9, R10 and R11 have the same meanings as in formula (I).
This reaction is preferably carried out in the presence of a condensing agent which is used in peptide chemistry such as a carbodiimide (for example 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide or N,Nxe2x80x2-dicyclohexylcarbodiimide) or N,Nxe2x80x2-carbonyldiimidazole, in an inert solvent such as an ether (tetrahydrofuran or dioxane for example), an amide (dimethylformamide) or a chlorinated solvent (methylene chloride, 1,2-dichloroethane or chloroform for example) at a temperature of between 0xc2x0 C. and the boiling temperature of the reaction mixture, or after prior binding of the acid to a resin of the TFP type of formula: 
in which S represents an aminopolystyrene resin, in an inert solvent such as dimethylformamide, in the presence of 4-dimethylaminopyridine, at a temperature close to 20xc2x0 C. The binding to the resin is generally carried out in dimethylformamide, in the presence of 4-dimethylaminopyridine and 1,3-diisopropylcarbodiimide, at a temperature close to 20xc2x0 C.
The compounds of formula (I) for which R2 and/or R3 and/or R4 represent an aromatic or a heteroaromatic substituted with xe2x80x94COxe2x80x94NHxe2x80x94NR6R7 may also be prepared by reacting a corresponding compound of formula (I) for which R2 and/or R3 and/or R4 represent an aromatic or a heteroaromatic substituted with xe2x80x94COOR5 and R5 represents an alkyl or phenyl radical optionally substituted with halogens, with a hydrazine H2Nxe2x80x94NR6R7 for which R6 and R7 have the same meanings as in formula (I).
This reaction is generally carried out in an inert solvent such as dimethylformamide, at a temperature close to 20xc2x0 C.
The compounds of formula (I) for which R2 represents an aromatic or a heteroaromatic substituted with xe2x80x94COxe2x80x94NHR9 in which R9 represents a hydrogen atom and/or R3 and/or R4 represent an aromatic or a heteroaromatic substituted with xe2x80x94COxe2x80x94NR10R11 in which R10 and R11 are hydrogen atoms may also be prepared by hydrolysis of a corresponding compound of formula (I) for which R2 and/or R3 and/or R4 represent an aromatic or a heteroaromatic substituted with cyano.
This reaction is carried out by any known method which makes it possible to pass from a nitrile to the corresponding carbamoyl without affecting the rest of the molecule. Preferably, the procedure is carried out using hydrochloric acid, in acetic acid, at a temperature close to 20xc2x0 C.
The compounds of formula (I) for which R2 represents an aromatic substituted with xe2x80x94O-alk-NR12R13 may also be prepared by reacting a derivative of formula (IX) for which R represents a chain Cxe2x95x90C(SO2R1)xe2x80x94Rxe2x80x22 or C(ORxe2x80x2)CH(SO2R1)Rxe2x80x22, Rxe2x80x2, R1, R2xe2x80x2, R3xe2x80x2 and R4xe2x80x2 have the same meanings as the substituents Rxe2x80x2, R1, R2, R3 and R4 of the formula (I) with the proviso that at least one of the substituents R2xe2x80x2, R3xe2x80x2 or R4xe2x80x2 represents an aromatic substituted with xe2x80x94O-alk-Hal in which alk represents an alkyl radical and Hal represents a halogen atom and, preferably, a chlorine or bromine atom, with an amine HNR12R13 in which R12R13 have the same meanings as in formula (I).
This reaction is generally carried out in an inert solvent such as acetonitrile, in the presence of an alkali metal carbonate (potassium carbonate for example), at a temperature close to 20xc2x0 C.
The derivatives of formula (IX) for which R represents a chain Cxe2x95x90C(SO2R1)Rxe2x80x22 or C(ORxe2x80x2)CH(SO2R1)Rxe2x80x22, Rxe2x80x2, R1, R2xe2x80x2, R3xe2x80x2 and R4xe2x80x2 have the same meanings as the substituents Rxe2x80x2, R1, R2, R3 and R4 of the formula (I) with the proviso that at least one of the substituents R2xe2x80x2, R3xe2x80x2 or R4xe2x80x2 represents an aromatic substituted with xe2x80x94O-alk-Hal in which alk represents an alkyl radical and Hal represents a halogen atom may be obtained by reacting a corresponding compound of formula (I) for which R2 represents an aromatic substituted with hydroxide with a Hal-alk-Hal derivative in which Hal represents a halogen.
This reaction is generally carried out in an inert solvent such as a ketone (methyl ethyl ketone for example), in the presence of a base such as an alkali metal carbonate (potassium carbonate for example), at the boiling temperature of the reaction medium.
The compounds of formula (I) for which R3 and/or R4 represents an aromatic substituted with -alk-NR6R7 may also be prepared by reacting a derivative of formula (IX) for which R represents a chain Cxe2x95x90C(SO2R1)Rxe2x80x22 or C(ORxe2x80x2)CH(SO2R1)Rxe2x80x22, Rxe2x80x2, R1, R2xe2x80x2, R3xe2x80x2 and R4xe2x80x2 have the same meanings as the substituents Rxe2x80x2, R1, R2, R3 and R4 of the formula (I) with the proviso that at least one of the substituents R3xe2x80x2 or R4xe2x80x2 represents a substituted aromatic -alk-Cl in which alk represents an alkyl radical with an amine HNR6R7 in which R6R7 have the same meanings as in formula (I).
This reaction is generally carried out in an inert solvent such as a chlorinated solvent (dichloromethane for example), optionally in the presence of a nitrogen base such as dimethylaminopyridine, diisopropylethylamine, at a temperature of between 5 and 25xc2x0 C.
The derivatives of formula (IX) in which R represents a chain Cxe2x95x90C (SO2R1)Rxe2x80x22 or C(ORxe2x80x2)CH(SO2R1)R2, Rxe2x80x2, R1, R2xe2x80x2, R3xe2x80x2 and R4xe2x80x2 have the same meanings as the substituents Rxe2x80x2, R1, R2, R3 and R4 of the formula (I) with the proviso that at least one of the substituents R3xe2x80x2 or R4xe2x80x2 represents an aromatic substituted with -alk-Cl may be obtained by reacting thionyl chloride with a corresponding compound of formula (I) for which at least one of the substituents R3 or R4 represents an aromatic substituted with one or more hydroxyalkyl radicals.
This reaction is generally carried out in an inert solvent such as a chlorinated solvent (dichloromethane for example), at a temperature of between 10 and 30xc2x0 C.
The compounds of formula (I) for which R represents a chain B, Rxe2x80x2 represents a hydrogen atom and R3 and/or R4 represents an aromatic substituted with hydroxyalkyl in which the alkyl residue contains one carbon atom may also be prepared by reacting diisobutylaluminum hydride with a corresponding compound of formula (I) for which R represents a chain B, Rxe2x80x2 represents a hydrogen atom and R3 and/or R4 represents an aromatic substituted with one or more xe2x80x94COOR5 radicals, in which R5 is an alkyl radical.
This reaction is generally carried out in toluene, at a temperature of between xe2x88x9230xc2x0 C. and 0xc2x0 C.
The compounds of formula (I) for which R2 represents a phenyl radical substituted with xe2x80x94NR6R7 representing a 1-piperazinyl ring substituted at the 4 position with an alkyl radical may also be prepared by reacting a corresponding compound of formula (I) for which R2 represents a phenyl radical substituted with a radical xe2x80x94NR6R7 representing a 1-piperazinyl ring with an alk-CHO derivative in which alk represents a straight- or branched-chain alkyl radical containing 1 to 5 carbon atoms.
This reaction is generally carried out in an inert solvent such as a chlorinated solvent (dichloroethane or chloroform for example), in the presence of NaBH(OCOCH3)3, at a temperature close to 20xc2x0 C.
The compounds of formula (I) for which R2 represents a phenyl radical substituted with xe2x80x94NR6R7 representing a 1-piperazinyl ring substituted at the 4 position with a radical xe2x80x94COOalk may also be prepared by reacting a corresponding compound of formula (I) for which R2 represents a phenyl radical substituted with a radical xe2x80x94NR6R7 representing a 1-piperazinyl ring with a derivative of formula Hal-COOalk in which alk represents an alkyl radical and Hal represents a halogen atom and, preferably, a chlorine atom.
This reaction is generally carried out in pyridine, at a temperature close to 20xc2x0 C.
The compounds of formula (I) for which R2 represents a phenyl radical substituted with xe2x80x94NR6R7 representing a 1-piperazinyl ring substituted at the 4 position with a radical xe2x80x94COxe2x80x94NHalk or xe2x80x94CSxe2x80x94NHalk may also be prepared by reacting a corresponding compound of formula (I) for which R2 represents a phenyl radical substituted with xe2x80x94NR6R7 representing a 1-piperazinyl ring with a derivative of formula Yxe2x95x90Cxe2x95x90Nalk in which alk represents a straight- or branched-chain alkyl radical containing 1 to 6 carbon atoms and Y represents a sulfur or oxygen atom.
This reaction is generally carried out in an inert solvent such as a chlorinated solvent (dichloromethane for example), at a temperature close to 20xc2x0 C.
The compounds of formula (I) for which R2 represents a phenyl radical substituted with a radical xe2x80x94NR6R7 representing a 1-piperazinyl ring substituted at the 4 position with a radical xe2x80x94CO-alk-NR14R15 may also be prepared by reacting a corresponding compound of formula (I) for which R2 represents a phenyl radical substituted with a radical xe2x80x94NR6R7 representing a 1-piperazinyl ring with an acid of formula R15R14N-alk-COOH in which alk represents an alkyl radical and R14 and R15 have the same meanings as in formula (I), optionally followed by deprotection of the product for which R14 is a tert-butoxycarbonyl radical in order to obtain the compounds for which R14 is a hydrogen atom.
This reaction is generally carried out in an inert solvent such as a chlorinated solvent (dichloroethane for example), at a temperature close to 20xc2x0 C. The deprotection is carried out using formic acid at a temperature close to 20xc2x0 C.
The compounds of formula (I) for which R2 represents a phenyl radical substituted with a radical xe2x80x94NR6R7 representing a 1-piperazinyl ring substituted at the 4 position with a radical xe2x80x94CO-alk in which alk represents a methyl radical may also be prepared by reacting a corresponding compound of formula (I) for which R2 represents a phenyl radical substituted with a radical xe2x80x94NR6R7 representing a 1-piperazinyl ring with acetic anhydride.
This reaction is generally carried out in the presence of pyridine, at a temperature close to 20xc2x0 C.
It is understood for persons skilled in the art that, to carry out the processes according to the invention which are described above, it may be necessary to introduce groups protecting amino, hydroxyl and carboxyl functions in order to avoid side reactions. These groups are those which allow removal without affecting the rest of the molecule. As examples of groups protecting the amino function, there may be mentioned tert-butyl or methylcarbamates which may be regenerated using iodotrimethylsilane or allyl using palladium catalysts. As examples of groups protecting the hydroxyl function, there may be mentioned triethylsilyl and tert-butyldimethylsilyl which may be regenerated using tetrabutylammonium fluoride or alternatively asymmetric acetals (methoxymethyl or tetrahydropyranyl for example) with regeneration using hydrochloric acid. As groups protecting carboxyl functions, there may be mentioned esters (allyl or benzyl for example), oxazoles and 2-alkyl-1,3-oxazolines. Other protecting groups which can be used are described by GREENE T. W. et al., Protecting Groups in Organic Synthesis, second edition, 1991, John Wiley and Sons.
The compounds of formula (I) may be purified by the customary known methods, for example by crystallization, chromatography or extraction.
The enantiomers of the compounds of formula (I) may be obtained by resolution of the racemates for example by chromatography on a chiral column according to PIRCKLE W. H. et al., Asymmetric synthesis, Vol. 1, Academic Press (1983) or by formation of salts or by synthesis from chiral precursors. The diastereoisomers may be prepared according to known conventional methods (crystallization, chromatography or from chiral precursors).
The compounds of formula (I) may be optionally converted to addition salts with an inorganic or organic acid by the action of such an acid in an organic solvent such as an alcohol, a ketone, an ether or a chlorinated solvent. These salts also form part of the invention.
As examples of pharmaceutically acceptable salts, the following salts may be mentioned: benzenesulfonate, hydrobromide, hydrochloride, citrate, ethanesulfonate, fumarate, gluconate, iodate, isethionate, maleate, methane sulfonate, methylene-bis-xcex2-oxynaphtoate, nitrate, oxalate, pamoate, phosphate, salicylate, succinate, sulfate, tartrate, theophyllineacetate and p-toluenesulfonate.
The compounds of formula (I) exhibit advantageous pharmacological properties. These compounds possess a high affinity for the cannabinoid receptors and particularly those of the CB1 type. They are CBI receptor antagonists and are therefore useful in the treatment and prevention of disorders affecting the central nervous system, the immune system, the cardiovascular or endocrine system, the respiratory system, the gastrointestinal apparatus and reproductive disorders (Hollister, Pharm. Rev.; 38, 1986, 1-20, Reny and Sinha, Prog. Drug Res., 36, 71-114 (1991), Consroe and Sandyk, in Marijuana/Cannabinoids, Neurobiology and Neurophysiology, 459, Murphy L. and Barthe A. Eds, CRC Press, 1992) of bacterial, viral and parasitic infections.
Accordingly, these compounds may be used for the treatment or prevention of psychoses including schizophrenia, anxiety disorders, depression, epilepsy, neurodegeneration, cerebellar and spinocerebellar disorders, cognitive disorders, cranial trauma, panic attacks, peripheral neuropathies, glaucomas, migraine, Parkinson""s disease, Alzeimer""s disease, Huntington""s chorea, Raynaud""s syndrome, tremor, obsessive-compulsive disorder, senile dementia, thymic disorders, Tourette""s syndrome, tardive dyskinesia, bipolar disorders, cancers, movement disorders induced by medicaments, dystonia, endotoxemic shocks, hemorrhagic shocks, hypotension, insomnia, immunological diseases, multiple sclerosis, vomiting, asthma, appetite disorders (bulimia, anorexia), obesity, memory disorders, in weaning from chronic treatments and alcohol or drug abuse (opiods, barbiturates, cannabis, cocaine, amphetamine, phencyclide, hallucinogens, benzodiazepines for example), as analgesics or potentiators of the analgesic activity of the narcotic and nonnarcotic drugs. They may also be used for the treatment or prevention of intestinal transit disorders, as antibacterial, antiviral and antiparasitic agents.
The affinity of the compounds of formula (I) for the cannabis receptors has been determined according to the method described by KUSTER J. E., STEVENSON J. I., WARD S. J., D""AMBRA T. E., HAYCOCK D. A. in J. Pharmacol. Exp. Ther., 264 1352-1363 (1993).
In this test, the IC50 of the compounds of formula (I) is less than or equal to 100 nM.
Their antagonist activity has been shown by means of the model of hypothermia induced by an agonist of the cannabis receptors (CP-55940) in mice, according to the method described by Pertwee R. G. in Marijuana, Harvey D. J. eds, 84 Oxford IRL Press, 263-277 (1985).
In this text the ED50 of the compounds of formula (I) is less than or equal to 50 mg/kg.
The compounds of formula (I) exhibit low toxicity. Their LD50 is greater than 40 mg/kg by the subcutaneous route in mice.
The preferred compounds of formula (I) are those for which
R represents a chain (A) or (B) and Rxe2x80x2 represents a hydrogen atom or a xe2x80x94COalk radical,
R1 represents a methyl or ethyl radical,
R2 represents either an aromatic chosen from phenyl and naphthyl, these aromatics being nonsubstituted or substituted with one or more halogens, alkyl, alkoxy, hydroxyl, xe2x80x94COOR5, trifluoromethyl, trifluoromethylsulfanyl, trifluoromethoxy, xe2x80x94NR6R7, xe2x80x94COxe2x80x94NHxe2x80x94NR6R7, cyano, xe2x80x94CONHR9, alkylsulfanyl, hydroxyalkyl, nitro, xe2x80x94COxe2x80x94NR16R17, xe2x80x94O-alkNR12R13 or alkylthioalkyl or a heteroaromatic chosen from isoquinolyl, pyridyl, quinolyl, 1,2,3,4-tetrahydroisoquinolyl, 1,2,3,4-tetrahydroquinolyl and thienyl, these heteroaromatics being unsubstituted or substituted with a halogen, alkyl, alkoxy, xe2x80x94COOR5, trifluoromethyl, trifluoromethylsulfanyl, trifluoromethoxy, xe2x80x94NR6R7, xe2x80x94COxe2x80x94NHxe2x80x94NR6R7, cyano, xe2x80x94CONHR9, alkylsulfanyl, hydroxyalkyl, nitro or alkylthioalkyl,
R3 and R4, which are identical or different, represent either an aromatic chosen from phenyl or naphthyl, these aromatics being nonsubstituted or substituted with one or more halogens, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, xe2x80x94CONR10R11, -alk-NR6R7, hydroxyalkyl, formyl or xe2x80x94COOR5, or a heteroaromatic chosen from thiazolyl or thienyl rings, these heteroaromatics being unsubstituted or substituted with a halogen, alkyl, alkoxy, xe2x80x94CONR10R11, -alk-NR6R7, hydroxyalkyl or xe2x80x94COOR5.
R5 is alkyl or phenyl which is optionally substituted with one or more halogens,
R6 and R7, which are identical or different, represent a hydrogen atom or an alkyl, xe2x80x94COOalk, cycloalkyl, alkylcycloalkyl,-alk-O-alk or hydroxyalkyl radical or alternatively R6 and R7 together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated or unsaturated mono- or bicyclic heterocycle optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl, xe2x80x94COalk, xe2x80x94COOalk, xe2x80x94COxe2x80x94NHalk, xe2x80x94CSxe2x80x94NHalk, xe2x80x94CO-alk-NR14R15, oxo, hydroxyalkyl, alk-O-alk or xe2x80x94CO-NH2 radicals,
R9 represents a hydrogen atom or an alkyl radical or an alkyl radical substituted with dialkylamino, phenyl, cycloalkyl (optionally substituted with xe2x80x94COOalk) or a 3- to 10-membered saturated or unsaturated mono- or bicyclic heterocycle optionally containing one or more heteroatoms chosen from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl radicals,
R10 and R11, which are identical or different, represent a hydrogen atom or an alkyl radical or alternatively R10 and R11 together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated mono- or bicyclic heterocycle optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with an alkyl radical, R12 and R13, which are identical or different, represent a hydrogen atom or an alkyl or cycloalkyl radical or alternatively R12 and R13 together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated mono- or bicyclic heterocycle optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with an alkyl, xe2x80x94COalk, xe2x80x94COOalk, xe2x80x94COxe2x80x94NHalk, xe2x80x94CSxe2x80x94NHalk or xe2x80x94CO-alk-NR14R15 radical or a 3- to 10-membered saturated mono- or bicyclic heterocycle containing a heteroatom chosen from oxygen, sulfur and nitrogen,
R14 and R15, which are identical or different, represent a hydrogen atom or an alkyl or xe2x80x94COOalk radical,
R16 and R17 together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated mono- or bicyclic heterocycle optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen, alk represents an alkyl or alkylene radical, their optical isomers and their salts with an inorganic or organic acid.
The compounds of formula (I) which are particularly preferred are those for which
R represents a chain (A) or (B),
Rxe2x80x2 representing a hydrogen atom or a radical xe2x80x94COalk,
R1 represents a methyl or ethyl radical,
R2 represents either an aromatic chosen from
naphthyl,
phenyl,
phenyl substituted with one or more halogen, alkyl, alkoxy, hydroxyl, xe2x80x94COOR5 (in which R5 represents an alkyl or phenyl radical optionally substituted with several halogens) trifluoromethyl, trifluoromethylsulfanyl, trifluoromethoxy, xe2x80x94NR6R7 (in which R6 and R7, which are identical or different, represent a hydrogen atom or an alkyl or xe2x80x94COOalk radical or alternatively R6 and R7 together form with the nitrogen atom to which they are attached a heterocycle chosen from pyrrolidinyl, piperidyl, piperazinyl or piperazinyl substituted with one or more alkyl, xe2x80x94COalk, xe2x80x94COOalk, xe2x80x94COxe2x80x94NHalk, xe2x80x94CSxe2x80x94NHalk or xe2x80x94CO-alk-NR14R15 radicals, in which R14 and R15, which are identical or different, represent a hydrogen atom or an alkyl radical), xe2x80x94COxe2x80x94NHxe2x80x94NR6R7 (R6 and R7, which are identical or different, represent a hydrogen atom or an alkyl radical or alternatively R6 and R7 together form with the nitrogen atom to which they are attached a heterocycle chosen from piperidyl, piperazinyl or piperazyl substituted with one or more alkyl radicals), cyano, xe2x80x94CONHR9 (in which R9 represents a hydrogen atom or an alkyl radical or an alkyl radical substituted with dialkylamino, phenyl, cycloalkyl (optionally substituted with xe2x80x94COOalk) or a heterocycle chosen from pyrrolidinyl (optionally substituted with alkyl), tetrahydrofuryl, or morpholinyl), alkylsulfanyl, hydroxyalkyl, nitro, xe2x80x94COxe2x80x94NR16R17, (in which R16 and R17 together form with the nitrogen atom to which they are attached a piperidyl ring), xe2x80x94O-alkNR12R13 (in which R12 and R13 together form with the nitrogen atom to which they are attached a morpholino ring) or alkylthioalkyl,
or a heteroaromatic chosen from
isoquinolyl,
pyridyl,
quinolyl,
1,2,3,4-tetrahydroisoquinolyl,
1,2,3,4-tetrahydroquinolyl,
thienyl, or
thienyl substituted with a xe2x80x94COOR5 (in which R5 represents an alkyl radical) or xe2x80x94CONHR9, (in which R9 represents an alkyl radical),
R3 and R4, which are identical or different, represent either an aromatic chosen from
phenyl or
phenyl substituted with one or more halogen, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, hydroxyalkyl, formyl, xe2x80x94COOR5 (in which R5 is an alkyl radical), xe2x80x94CONR10R11 (in which R10 and R11, which are identical or different, represent a hydrogen atom or an alkyl radical), -alk-NR6R7 (in which R6 and R7, which are identical or different, represent a hydrogen atom or an alkyl, cycloalkyl, -alk-O-alk or hydroxyalkyl radical or alternatively R6 and R7 together form with the nitrogen atom to which they are attached a heterocycle chosen from piperidyl (optionally substituted with alkyl or oxo), pyrrolidinyl (optionally substituted with alkyl, hydroxyalkyl, -alk-O-alk or xe2x80x94COxe2x80x94NH2), thiomorpholinyl, morpholinyl, pyrrolyl, piperazinyl optionally substituted with oxo, alkyl, hydroxyalkyl, xe2x80x94COOR5 (in which R5 is an alkyl radical),
or a heteroaromatic chosen from
thiazolyl or
thienyl,
alk represents an alkyl or alkylene radical, their optical isomers and their salts with an inorganic or organic acid.
Preferably, R2 is a substituted phenyl radical, the latter is monosubstituted and, in particular, at the 3-position or alternatively disubstituted and, in particular at the 3,5, 2,5 or 2,3-positions.
Preferably, when R3 is a substituted phenyl radical, the latter is monosubstituted and, in particular, at the 4-position or disubstituted and, in particular, at the 2,4-positions.
Preferably, when R4 is a substituted phenyl radical, the latter is monosubstituted and, in particular, at the 4-position or disubstituted and, in particular, at the 2,4-positions.
The following compounds may be mentioned among the preferred compounds:
1-benzhydryl-3-[(methylsulfonyl)(phenyl)methylene]azetidine,
1-benzhydryl-3-[(3-methylphenyl)(methylsulfonyl)methylene]azetidine,
1-benzhydryl-3-[(3-chlorophenyl)(methylsulfonyl)methylene]azetidine,
1-benzhydryl-3-[(3,5-dichlorophenyl)(methylsulfonyl)methylene]azetidine,
1-benzhydryl-3-[(2,5-dichlorophenyl)(methylsulfonyl)methylene]azetidine,
1-benzhydryl-3-[(2,3-dichlorophenyl)(methylsulfonyl)methylene]azetidine,
1-benzhydryl-3-[(3-fluorophenyl)(methylsulfonyl)methylene]azetidine,
1-benzhydryl-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-benzhydryl-3-[(3-bromophenyl)(methylsulfonyl)methylene]azetidine,
1-benzhydryl-3-[(3-iodophenyl)(methylsulfonyl)methylene]azetidine,
1-benzhydryl-3-[(methylsulfonyl)(3-trifluoromethoxyphenyl)methylene]azetidine,
1-benzhydryl-3-[(methylsulfonyl)(3-trifluoromethylphenyl)methylene]azetidine,
1-benzhydryl-3-{[3,5-bis(trifluoromethyl)phenyl](methylsulfonyl)methylene}azetidine,
1-benzhydryl-3-[(3,5-dibromophenyl)(methylsulfonyl)methylene]azetidine,
1-benzhydryl-3-[(3-methoxycarbonylphenyl)(methylsulfonyl)methylene]azetidine,
1-benzhydryl-3-[(3-cyanophenyl)(methylsulfonyl)methylene]azetidine,
1-benzhydryl-3-[(3-cyanophenyl)(methylsulfonyl)methylene]azetidine,
1-benzhydryl-3-[(3-carbamoylphenyl)(methylsulfonyl)methylene]azetidine,
1-benzhydryl-3-[(methylsulfonyl)(naphth-1-yl)(methylsulfonyl)methylene]azetidine,
1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-[bis(4-methoxyphenyl)methyl]-3-[(3,5-difluorophenyl)-(methylsulfonyl)methylene]azetidine,
1-[bis(4-methylphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
(RS)-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]1-[(4-methoxyphenyl)(phenyl)methyl)]azetidine,
(R)-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]-1-[(4-methoxyphenyl)(phenyl)methyl)]azetidine,
(S)-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]-1-[(4-methoxyphenyl)(phenyl)methyl)]azetidine,
1-[bis(4-trifluoromethoxyphenyl)methyl]-3-[(3,5-difluorophenyl(methylsulfonyl)methylene]azetidine,
1-[bis(4-trifluoromethylphenyl)methyl]-3-[(3,5-difluorophenyl(methylsulfonyl)methylene]azetidine,
1-[bis(4-chlorophenyl)methyl]-3-{[(3,5-bis-(trifluoromethyl)phenyl]methylsulfonylmethylene}azetidine,
(RS)-1-[(4-chlorophenyl)(2,4-dichlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
(R)-1-[(4-chlorophenyl)(2,4-dichlorophenyl)methyl]3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
(S)-1-[(4-chlorophenyl)(2,4-dichlorophenyl)methyl]3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
(RS)-1-{(4-chlorophenyl)[4-hydroxymethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
(R)-1-{(4-chlorophenyl)[4-(hydroxymethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
(S) 1-{(4-chlorophenyl)[4-(hydroxymethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
(RS)-1-{(4-chlorophenyl)[4-(pyrrolidylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
(R)-1-{(4-chlorophenyl)[4-(pyrrolidylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
(S)-1-{(4-chlorophenyl)[4-(pyrrolidylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1{-(RS)-(4-chlorophenyl)[4-(3,3-dimethylpiperidin-1-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{(R)-(4-chlorophenyl)[4-(3,3-dimethylpiperidin-1-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{(S)-(4-chlorophenyl)[4-(3,3-dimethylpiperidin-1-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{(RS)-(4-chlorophenyl)[4-(thiomorpholin-4-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{(R)-(4-chlorophenyl)[4-(thiomorpholin-4-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{(S)-(4-chlorophenyl)[4-(thiomorpholin-4-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{(RS)-(4-chlorophenyl)[4-(N-ethyl-N-cyclohexylaminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{(R)-(4-chlorophenyl)[4-(N-ethyl-N-cyclohexylaminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{(S)-(4-chlorophenyl)[4-(N-ethyl-N-cyclohexylaminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{{(RS)-(4-chlorophenyl){4-[(4-ethoxycarbonylpiperazinyl)methyl]phenyl}methyl}}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{{(R)-(4-chlorophenyl)(4-[(4-ethoxycarbonylpiperazinyl)methyl]phenyl}methyl}}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{{(S)-(4-chlorophenyl){4-[(4-ethoxycarbonylpiperazinyl)methyl]phenyl}methyl}}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{(RS)-(4-chlorophenyl)[4-(N-cyclopropyl-N-propylaminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{1(R)-(4-chlorophenyl)[4-(N-cyclopropyl-N-propylaminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{(S)-(4-chlorophenyl)[4-(N-cyclopropyl-N-propylaminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{(RS)-(4-chlorophenyl)[4-(diisopropylaminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{(R)-(4-chlorophenyl)[4-(diisopropylaminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{(S)-(4-chlorophenyl)[4-(diisopropylaminomethyl)phenyl]methyl}-3-(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{{(RS)-(4-chlorophenyl){4-[bis-(2-methoxyethyl)aminomethyl]phenyl}methyl}}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{{(R)-(4-chlorophenyl){4-[bis-(2-methoxyethyl)aminomethyl]phenyl}methyl}}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{{(S)-(4-chlorophenyl){4-[bis-(2-methoxyethyl)aminomethyl]phenyl}methyl}}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{(RS)-(4-chlorophenyl)[4-(di-n-propylaminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{(R)-(4-chlorophenyl)[4-(di-n-propylaminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{(S)-(4-chlorophenyl)[4-(di-n-propylaminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{(RS)-(4-chlorophenyl)[4-(piperidin-1-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine
1-{(R)-(4-chlorophenyl)[4-(piperidin-1-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine
1-{(S)-(4-chlorophenyl)[4-(piperidin-1-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{(RS)-(4-chlorophenyl)[4-(4-methylpiperazin-1-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{(R)-(4-chlorophenyl)[4-(4-methylpiperazin-1-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{(S)-(4-chlorophenyl)[4-(4-methylpiperazin-1-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{(RS)-(4-chlorophenyl)[4-(morpholin-4-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{(R)-(4-chlorophenyl)[4-(morpholin-4-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{(S)-(4-chlorophenyl)[4-(morpholin-4-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{(RS)-(4-chlorophenyl)[4-(diethylaminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{(R)-(4-chlorophenyl)[4-(diethylaminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{(S)-(4-chlorophenyl)[4-(diethylaminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{(RS)-(4-chlorophenyl)[4-(piperazin-2-on-4-yl-methyl)phenyl]methyl}-3-[3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{(R)-(4-chlorophenyl)[4-(piperazin-2-on-4-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{(S)-(4-chlorophenyl)[4-(piperazin-2-on-4-yl-methyl)phenyl]methyl}-3-[3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{(RS)-(4-chlorophenyl)[4-(imidazol-1-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{(R)-(4-chlorophenyl)[4-(imidazol-1-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{(S)-(4-chlorophenyl)[4-(imidazol-1-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
(RS)-1-{(4-chlorophenyl)[4-(N,N-dimethylcarbamoyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
(R)-1-{(4-chlorophenyl)[4-(N,N-dimethylcarbamoyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
(S)-1-{(4-chlorophenyl)[4-(N,N-dimethylcarbamoyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
(RS)-1-{(4-chlorophenyl)[4-(N-ethylcarbamoyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
(R)-1-{(4-chlorophenyl)[4-(N-ethylcarbamoyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
(S)-1-{(4-chlorophenyl)[4-(N-ethylcarbamoyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
(RS)-1-[(4-carbamoylphenyl)(4-chlorophenyl)methyl]3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
(R)-1-[(4-carbamoylphenyl)(4-chlorophenyl)methyl]3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
(S)-1-[(4-carbamoylphenyl)(4-chlorophenyl)methyl]3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-[bis(4-chlorophenyl)methyl]-3-[(3,5-dichlorophenyl)(methylsulfonyl)methylene]azetidine,
1-benzhydryl-3-[(3-methylsulfanylphenyl)(methylsulfonyl)methylene]azetidine,
1-benzhydryl-3-[(3-methylsulfanylmethyl)phenyl)](methylsulfonyl)methylene]azetidine,
1-[bis(4-chlorophenyl)methyl]-3-[(3-cyanophenyl)(methylsulfonyl)methylene]azetidine,
1-[bis(4-chlorophenyl)methyl]-3-[(3-carbamoylphenyl)(methylsulfonyl)methylene]azetidine,
1-[bis(4-chlorophenyl)methyl]-3-[(3-methoxyphenyl)(methylsulfonyl)methylene]azetidine,
1-[bis(4-chlorophenyl)methyl]-3-[(3-hydroxyphenyl)(methylsulfonyl)methylene]azetidine,
1-[bis(4-chlorophenyl)methyl]-3-[(3-methylsulfonyl)-(3-pyrrolidinylphenyl)methylene]azetidine,
1-[bis(4-chlorophenyl)methyl]-3-[(3-hydroxymethylphenyl)(methylsulfonyl)methylene]azetidine,
1-[bis(4-chlorophenyl)methyl]3-{(methylsulfonyl)[3-(N-piperidylcarbamoyl)phenyl]methylene}azetidine,
1-[bis(4-chlorophenyl)methyl]-3-[(methylsulfonyl)-(3-trifluoromethylsulfanylphenyl)(methylsulfonyl)methylene]azetidine,
1-[bis(4-fluorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-[bis(2-fluorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-[bis(3-fluorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
(RS)-1-[(4-chlorophenyl)(thiazol-2-yl)methyl]-3-[(methylsulfonyl)(phenyl)methylene]azetidine,
(R)-1-[(4-chlorophenyl)(thiazol-2-yl)methyl]-3-[(methylsulfonyl)(phenyl)methylene]azetidine,
(S)-1-[(4-chlorophenyl)(thiazol-2-yl)methyl]-3-[(methylsulfonyl)(phenyl)methylene]azetidine,
(RS)-1-[(4-chlorophenyl)(thien-2-yl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
(R)-1-[(4-chlorophenyl)(thien-2-yl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
(S)-1-[(4-chlorophenyl)(thien-2-yl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-benzhydryl-3-[(ethylsulfonyl)(phenyl)methylene]azetidine,
1-[bis(4-chlorophenyl)methyl]-3-{{3-[N-(4-methylpiperazinyl)carbamoyl]phenyl}(methylsulfonyl)-methylene]azetidine,
1-[bis(4-chlorophenyl)methyl]-3-{[3-(2,2-dimethylcarbohydrazido)phenyl](methylsulfonyl)-methylene}azetidine,
1-[bis(thien-2-yl)methyl]-3-[3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-[bis(p-tolyl)methyl]-3-[(methylsulfonyl)(phenyl)methylene]azetidine,
1-[4-chlorophenyl)(4-hydroxymethylphenyl)methyl]3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-[bis(4-chlorophenyl)methyl]-3-[(3-methylaminophenyl)(methylsulfonyl)methylene]azetidine,
(RS)-1-[(4-chlorophenyl)(thiazol-2-yl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
(R)-1-[(4-chlorophenyl)(thiazol-2-yl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
(S)-1-[(4-chlorophenyl)(thiazol-2-yl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-[bis(4-chlorophenyl)methyl]-3-[(methylsulfonyl)(2-methoxycarbonylthien-5-yl)methylene]azetidine,
1-[bis(4-chlorophenyl)methyl]-3-hydroxy-3-[(methylsulfonyl)(2-methoxycarbonylthien-5-yl)methyl]azetidine(RS),
1-[bis(4-chlorophenyl)methyl]-3-[(2-isobutylaminocarbonylthien-5-yl)(methylsulfonyl)methylene]azetidine,
1-[bis(4-chlorophenyl)methyl]-3-[(3-methoxycarbonylphenyl)(methylsulfonyl)methyl-(RS)azetidin-3-ol,
1-[bis(4-chlorophenyl)methyl]-3-[(methylsulfonyl)(pyridin-4-yl)methyl-(RS)azetidin-3-ol,
1-[bis(4-chlorophenyl)methyl]-3-[(methylsulfonyl)(pyridin-3-yl)methyl-(RS)azetidin-3-ol,
3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N-(3-morpholin-4-yl-propyl)benzamide,
3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N-(3-dimethylaminopropyl)benzamide,
3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N-(2-pyrrolidin-1-ylethyl)benzamide,
3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N-(2-dimethylamino-1-methylethyl)benzamide,
3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N-piperidin-1-ylbenzamide,
3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N-isobutylbenzamide,
3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N-(3-imidazol-1-ylpropyl)benzamide,
3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N-(2-dimethylaminoethyl)benzamide,
3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)benzoic acid Nxe2x80x2-methylhydrazide,
3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N-(2-morpholin-4-ylethyl)benzamide,
3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N-(1-ethylpyrrolidin-2-ylmethyl)benzamide,
3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N-(2,2-dimethylpropyl)benzamide,
3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N-cyclohexylmethylbenzamide,
3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N-cyclopropylmethylbenzamide,
3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N-(2-methylbutyl)benzamide,
3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N-(2-phenylpropyl)benzamide,
3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N-(tetrahydrofuran-2-ylmethyl)benzamide,
3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N-(2,2-diphenylethyl)benzamide,
3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N-(2-ethylbutyl)benzamide,
4-{[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)benzoylamino]methyl}cyclohexanecarboxylic acid methyl ester,
2-amino-1-{4-[3-({1-[bis-(4-chlorophenyl]methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazin-1-yl}ethanone,
(2-{4-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazin-1-yl}-2-oxoethyl)carbamic acid tert-butyl ester,
1-{4-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazin-1-yl}-2-methylaminoethanone,
(2-(4-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazin-1-yl}-2-oxoethyl)-N-methylcarbamic acid tert-butyl ester,
4-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine-1-carbothioic acid N-methylamide,
4-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine-1-carboxylic acid N-methylamide,
4-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine-1-carboxylic acid methyl ester,
1-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]-4-isobutylpiperazine,
1-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]-4-ethylpiperazine,
4-acetyl1-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine,
1-{4-(3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazin-1-yl}-2-dimethylaminoethanone,
1-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine,
4-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine-1-carboxylic acid tert-butyl ester,
1-[bis(4-methoxycarbonylphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
3-acetoxy-1-[bis(4-methoxycarbonylphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)azetidine,
(RS)-4-[4-((4-chlorophenyl){3-[(3,5-difluorophenyl)methanesulfonylmethylene]azetidin-1-yl}methyl)benzyl]morpholine,
4-(4-{3-[(1-benzhydrylazetidin-3-ylidene)methanesulfonylmethyl]phenoxy}butyl)morpholine,
4-(4-{3-[(1-benzhydrylazetidin-3-ylidene)methanesulfonylmethyl]phenoxy}propyl)morpholine,
their optical isomers and their esters.
Among these compounds, the following compounds are particularly preferred;
1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene(RS)]azetidin-3-ol,
3-acetoxy-1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl)methylsulfonylmethyl (RS)]azetidine
their optical isomers and their salts with an inorganic or organic acid.